tbuckley/cabot-search huggingface dataset:
A phase 1, multicenter, open-label, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10382 (TERN-701) in patients (pts) with chronic myeloid leukemia (CML).
Authors: Weiming Li, Na Xu, Zhongyuan Xu, Yanli Zhang, Junmin Li, Huanling Zhu, Li Zheng, Xiaojing Yan, Xin Du, Hongying Wei, Qiqi Huang, Jiawei Wei, Yu Hu
Journal: Journal of Clinical Oncology (2023)

TPS7081 Background: There is a need for new treatment options for pts with CML who are intolerant/resistant to currently available BCR-ABL1 ATP-binding site targeted tyrosine kinase inhibitors (TKIs). HS-10382 (TERN-701) is a potent, oral small molecule allosteric inhibitor of BCR-ABL. By binding to the myristoyl site of the BCR-ABL1 protein, HS-10382 (TERN-701) locks BCR-ABL1 into an inactive conformation. This results in a mutation-driven resistance profile different from that of ATP-binding site TKIs, providing potential for both monotherapy and combination therapy with ATP-binding site TKIs. In preliminary nonclinical assays, HS-10382 (TERN-701) was highly potent against wild type BCR-ABL1 as well as most common mutations acquired by pts treated with second generation active site TKIs. This ongoing first-in-human phase 1 study is evaluating HS-10382 (TERN-701) in pts with CML. Methods: Eligible adult CML chronic phase (CP) or advanced phase (AP) pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy are enrolled in an open-label Phase 1 study to evaluate the safety, tolerability, PK and efficacy of HS-10382 (TERN-701). This study is being conducted in two parts: Part 1 dose escalation utilizing a rolling six design and Part 2 dose expansion. In the dose escalation stage, CML-CP/AP pts who are resistant or intolerant to prior BCR-ABL-1 therapy are being enrolled to determine the maximum tolerated dose (MTD) or maximum applicable dose. Doses selected from the escalation part will be evaluated in the expansion stage in CML-CP pts who are resistant or intolerant to prior BCR-ABL-1 TKI therapy and have no T315I mutation. All pts will be carefully followed for adverse events for the duration of study treatment and for 28 days after the last dose of study drug. Pts will be permitted to continue therapy with assessments for progression if the study drug is well-tolerated and the pt has no objective evidence of disease progression. This study is ongoing (enrollment underway for Part 1, dose 3 as of February 2023) with 7 participating study sites in China. Clinical trial information: NCT05367700 .
Characterizing non-small cell lung cancer driven by mutations in ARAF and CRAF family members.
Authors: Tamio Okimoto, Joseph Amann, Andrew Elliott, Stephen V. Liu, Patrick C. Ma, Ari M. Vanderwalde, Milan Radovich, George W. Sledge, Vincenzo Coppola, David Paul Carbone
Journal: Journal of Clinical Oncology (2023)

e15085 Background: Cancer genome screening is becoming standard clinical practice, but the number of actionable mutations detected is limited. To expand on our previous report of the possibility that ARAF S214C and CRAF S257L located in the conserved region 2 (CR2) were actionable driver mutations, we investigated responses to targeted therapies in mouse models and the prevalence of these alterations across many cancer types represented in a large real-world database of molecularly profiled patient tumors. Methods: Conditional transgenic mice that expressed human ARAF S214C or CRAF S257L in their lungs were established and treated with sorafenib or trametinib. Activation of the MAPK pathway following sorafenib or trametinib treatment was assessed in vitro by phospho-ERK IHC. DNA sequencing (592-gene or whole exome) was performed for patient samples submitted to Caris Life Sciences (Phoenix, AZ), and the prevalence of ARAF/CRAF variants was determined for each cancer type. Results: Both ARAF S214C and CRAF S257L dimerized to activate the MAPK pathway. Although a low concentration of sorafenib promoted ERK phosphorylation, a high concentration of sorafenib inhibited ERK phosphorylation. Transgenic mice rapidly developed lung adenocarcinoma when the mutant proteins were expressed. Sorafenib treatment induced tumor necrosis in both ARAF- and CRAF-mutated tumors, and 3 months of sorafenib treatment prolonged the survival of CRAF-mutant mice. Pan-tumor analysis of real-world patient samples revealed that ARAF and CRAF mutations in CR2 were found in 0.125% and 0.234% of tumors, respectively. ARAF mutations in CR2 were found in 0.415% of cholangiocarcinoma, 0.132% of colorectal cancer, and 0.173% of non-small cell lung cancer (NSCLC). CRAF mutations in CR2 were found in 0.509% of colorectal cancer, 0.502% of gastric cancer, 0.303% of NSCLC, and 0.978% of melanoma. The most prevalent CR2 mutations were ARAF S214F and CRAF S257L. Conclusions: Our in vitro results suggest ARAF S214C and CRAF S257L mutations are rare driver mutations that may be effectively treated with RAF inhibitors and warrant further investigation. [Table: see text]
Pharmacokinetics and pharmacodynamics of proposed denosumab biosimilar and reference denosumab in healthy male subjects.
Authors: Barbara Vogg, Johann Poetzl, Rachid El Galta, Rainard Fuhr, Arnd Schwebig, Susmit Sekhar
Journal: Journal of Clinical Oncology (2023)

e14500 Background: Denosumab is a human monoclonal antibody that binds to RANKL, preventing activation of its receptor RANK on the surface of osteoclasts and inhibiting osteoclastic bone resorption. This study was conducted to support demonstration of biosimilarity by evaluating similarity in pharmacokinetics (PK), pharmacodynamics (PD), safety, and immunogenicity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab in healthy male subjects. Methods: This double-blind, three-arm, parallel-group, PK and PD study was conducted at two centres in Germany. Participants were randomised (1:1:1) to receive a single 35 mg s.c. dose of either GP2411, EU-authorised reference denosumab, or US-licensed reference denosumab and were followed-up for 39 weeks. A sub-therapeutic dose was chosen since it is more sensitive than therapeutic doses to detect potential PK and PD differences; PK and PD similarity established at the 35 mg dose supports extrapolation to therapeutic doses. The study enrolled 502 healthy male subjects, aged 28–65 years, with a body weight range of 50–90 kg. PK endpoints included the area under the serum concentration-time curve measured from the time of dosing and extrapolated to infinity (AUC inf ), or to the last measurable concentration (AUC last ), and maximum observed serum concentration (C max ). PD endpoints were the area under the effect-time curve (AUEC) of the percentage change from baseline (%CfB) in serum carboxy-terminal crosslinked telopeptide of type I collagen (CTX), and CTX and procollagen I N-terminal propeptide (PINP) serum concentration per visit. Results: Overall, 499 healthy volunteers received one of the three treatments. PK and PD similarity was demonstrated between GP2411 and its reference biologic (EU-authorised and US-licensed), as the 90% CIs and 95% CIs of the geometric mean ratios for PK and PD parameters were fully contained within the prespecified equivalence margins [0.80, 1.25]. Changes from baseline to Week 39 in serum concentrations of CTX and PINP were similar between groups. Conclusions: PK and PD similarity between GP2411, a proposed Sandoz denosumab biosimilar, and reference denosumab were demonstrated in healthy male subjects. [Table: see text]
Distribution of non-Hodgkin lymphomas across US: Are Hispanics any different from non-Hispanics?
Authors: Daniela Urueta Portillo, Joel Michalek, Qianqian Liu, Adolfo Enrique Diaz Duque
Journal: Journal of Clinical Oncology (2023)

e18619 Background: Non-Hodgkin lymphoma (NHL) encompasses various subtypes that differ in incidence, etiology, clinical features, and survival. NHL subtypes can be divided into B-cell and T-cell lymphomas, when classifying them based on cell of origin. The distribution of NHL subtypes has been known to variate between geographic locations, and always results are reported without classifying them among ethnicities. Hispanics are by now, the largest ethnic minority in US, according to the latest 2020 US Census, and it is of utmost importance to understand variations related to ethnicity. This is to our knowledge, the largest retrospective study comparing NHL frequency of subtypes in Hispanics vs Non-Hispanics. Methods: Data were analyzed on NHL patients in the US and reported to the Surveillance, Epidemiology, and End Results (SEER) 18 database between 2000 and 2018. SEER 18 contains the most comprehensive population-based cancer information in the US, covering approximately 27% of the US population and up to 36% of HI alone. Racial groups analyzed included NH whites and HI whites. Results: There were 366516 patients diagnosed with NHL over the 8-year study period included in our study. Most of these patients belong to the B-cell NHL type, comprising 91% of the group. The distribution of the major subtypes of NHL is shown in the pie charts. We noted differences in the distribution of major NHL subtypes among NH and H. Among the B-Cell NHL subtypes, Hispanics had higher proportions of DLBCL (42% vs. 31%), FL (19% vs. 17%), and Burkitt lymphoma (4% vs. 2%) than NH. On the contrary, a significant difference was found, with a higher presence of CLL/SLL in NH, which was seen in 31% vs. 15% in H. Within the T-Cell NHL subtypes, compared with non-Hispanics, Hispanics had higher proportions of NK/T cell lymphoma (11% vs. 3%) and anaplastic large cell lymphoma (15 vs. 12%) but a lower proportion of mycosis (26% vs. 30) in NH and cutaneous T-cell lymphoma (9% vs. 13%). The rest of the subtypes showed to have similar proportion rates. Conclusions: In conclusion, our study shows evidence of a significant difference in subtype distribution between NH and H patients. The involvement of a complex process in developing NHL and the etiologic heterogeneity among subtypes has been previously described. These differences in subtype distribution across races may be due to geographic location, genetic variants, occupational exposures, infectious conditions, family history, and socioeconomic status. Analyzing and comparing multiple cancer subtypes can provide critical clues for future epidemiological investigations to improve care among our minorities. Due to the growing Hispanic population in the US, it is significantly vital to represent the differences in subtype presentation graphically.
WTX212, an erythrocyte-anti-PD1 antibody conjugate, to demonstrate anti-tumor activities in tumor models and patients with cancer with acquired resistance to immunotherapy.
Authors: Nie Xiaoqian, Yuehua Liu, Yun Chen, Qi Zhang, Xiangmin Tong, Yanjie Huang, Yang Yuan, Jiawei Zheng, Li Xu, Xiaofei Gao
Journal: Journal of Clinical Oncology (2023)

e14529 Background: Despite the success of immune-checkpoint blockade (ICB) treatments, a considerable proportion of patients cannot benefit from ICB therapy due to acquired resistance. One major challenge is the systemic suppression of immune cells induced by the tumor. Recent studies have revealed that successful immunotherapy drives new immune responses arising from peripheral immune system instead of reinvigorating the pre-existing responses in the tumor. Here we designed WTX212, autologous engineered red blood cells (RBCs) conjugated with anti-PD1 antibodies capable of activating the peripheral immune system. We also evaluated its anti-cancer activities in anti-PD1 non-responsive tumor models and a first-in-human (FIH) trial. Methods: The anti-tumor efficacy of WTX212 was evaluated in both PD1 responsive (MC38 colorectal cancer) and non-responsive (KP lung cancer and pB3 breast cancer) mouse tumor models (n=7 / group). Mice were monitored twice a week for clinical signs and tumor sizes. The mechanism of action was investigated in splenectomized mice and by analyzing the biodistribution of WTX212 using a radiolabeling method. The immune landscape was also profiled through cytof mass and scRNA-seq analyses in the spleen, tumor and peripheral blood. The FIH trial (NCT05707325) explores safety, pharmacokinetics and mechanism in cancer patients with acquired resistance to ICB. WTX212 was manufactured by covalently engineering anti-PD1 antibody with RBCs isolated from patients. By 6 th Feb 2023, 3 patients have been enrolled and received at least one dose of WTX212 (20*10 10 cells, IV, Q3W). Results: Treatment of WTX212 significantly suppressed tumor growth up to 100% in anti-PD1 responsive and non-responsive tumor models and activated tumor microenvironment with increased infiltrated T cells. Unlike antibodies, WTX212 primarily distributed to the spleen and vascular system. The anti-tumor effect of WTX212 was abrogated in corresponding splenectomized mice. Compared to anti-PD1 antibody, single-cell analysis identified the immune landscape remodeling in the spleen from WTX212-treated mice, with down-regulation of PD-L1+ myeloid-derived suppressor cells (MDSCs) and up-regulation of effector CD8+ T cells. In the FIH trial, 3 patients have been administered with total eight cycles of WTX212. No treatment-related AEs greater than Grade 2 were observed. WTX212 remained in the peripheral blood day 21 post transfusion. WTX212 rapidly activates peripheral immune systems with decreased MDSCs, Tregs and increased effector T cells in peripheral blood from all patients. Conclusions: WTX212 demonstrated anti-tumor activities by activating the peripheral immune system to overcome resistance to immunotherapy in both preclinical models and human patients. WTX212 is well-tolerated supporting the future clinical trials.
A novel prognostic model for oligometastatic renal cell carcinoma: COMPARZ study post-hoc analysis.
Authors: Aihetaimujiang Anwaier, Hailiang Zhang, Jiacui Yu, Hualin Wan, Su Miin Ong, Hao Zhe Tay, Dingwei Ye
Journal: Journal of Clinical Oncology (2023)

e16521 Background: International metastatic renal cell carcinoma database consortium (IMDC) is the most commonly used prognostic model for metastatic renal cell carcinoma (mRCC), however, its clinical application has been limited due to the cumbersome design and vague recommendation of treatment decisions for patients in the IMDC intermediate risk group. Previous studies indicated the favorable prognosis of oligometastatic RCC, but the definition of oligometastasis has not been clarified. This study aims to construct a new prognostic model of oligometastatic RCC based on the COMPARZ study cohort. Methods: Patients from the COMPARZ study (which was a randomized phase III non-inferiority study comparing pazopanib and sunitinib in advanced RCC or mRCC patients). Patients (N=1038) were divided into two cohorts for models construction respectively, Cohort A (n=293) with primary kidney tumor; Cohort B (n=745) without primary kidney tumor. Multivariate Cox regression analysis was performed to identify the independent prognostic risk factors for each model with overall survival (OS) as primary endpoint. Uno’s C-statistics was utilized to compare the novel risk model with IMDC risk. These models were then used to examine and stratify the patients in IMDC intermediate risk group. Results: In Cohort A, four risk factors were identified independent predictors for short survival. Patients were segregated into the oligo group and the non-oligo group. The concordance index (C-index) for Model A and IMDC risk model was 0.63 (95%CI: 0.59-0.67) and 0.65 (95%CI: 0.61-0.69), respectively (p=0.389). In Cohort B, three risk factors were identified as independent predictors of short survival. Patients were also divided into the oligo group and the non-oligo group. The C-index between Model B and IMDC risk model was 0.62 (95%CI: 0.59-0.64) and 0.61 (95%CI: 0.58-0.64), respectively (p=0.650). For Model A, mOS for non-oligo group was 13.4 months vs NR in oligo group (3y OS: 25.3 vs 51.8%), while for model B, mOS was 18.5 vs NR respectively (3y OS: 24.3 vs 57.5%). With the novel prognostic models, patients in the IMDC intermediate risk group could be further stratified into oligo group (mOS: NR; 3y OS: 55.6%) that had a better outcome than patients in non-oligo group (mOS: 19.2 month; 3y OS: 24.9%; p&lt;0.001). Conclusions: Compared with the current IMDC model, the novel prognostic models of oligometastatic mRCC could well distinguish patients into favorable and poor prognostic groups with fewer risk factors and comparable predictive power. Meanwhile, the novel models can better stratify the IMDC intermediate risk group into oligo and non-oligo groups with significantly different OS outcomes, and is more conductive to the comprehensive treatment of patients with mRCC.
Comparison of adjuvant capecitabine plus oxaliplatin (CAPOX) versus S-1 in patients with gastric cancer after gastrectomy based on the registry data base on the National Health Insurance Service (NHIS) database in Korea.
Authors: Chi Hoon Maeng, Hoseob Kim, Mina Kim
Journal: Journal of Clinical Oncology (2023)

e16069 Background: The standard of care for locally advanced gastric cancer in Asia is still upfront gastrectomy with D2 lymph node dissection followed by adjuvant chemotherapy (AC). Both capecitabine plus oxaliplatin (CAPOX) and S-1 are accepted. Which of the two types of chemotherapy is better is still controversial. Methods: For this retrospective nationwide cohort study, data were obtained from the NHIS of Korea. As the NHIS is a single-payer healthcare system, it covers the entire population in the Republic of Korea and it also provides comprehensive information which contains demographic data, healthcare utilization, pharmaceutical prescriptions, and death for each patient. In study population, we included patients who received gastrectomy with a primary diagnosis of gastric cancer which were certified by international classification of disease (ICD) 10th codes of C16.x from January 1st 2013 to December 31th 2018. Survival outcomes of patients who received postoperative chemotherapy were compared based on S-1 (Arm S) vs. CAPOX (Arm C) as well as other relevant clinical variables such as age, sex, co-morbidity and completion of planned treatment. Results: During the study period, 98,556 patients were identified to have undergone both gastric cancer and surgery. After excluding ineligible subjects, a total of 6,602 patients were included in the analysis. Of these, there were 4,199 in Arm S and 2,403 in Arm C, respectively. After propensity score matching, final study population were identified 2,067 in each arm. Arm C showed statistically inferior survival (OS) compared to Arm S (5-year OS rate, 84.0% vs 90.0%, p &lt; 0.0001). Disease-free survival (DFS) was also shorter in Arm C than Arm S (5-year DFS, 78.4% vs 86.1%, p &lt; 0.0001). Age (65 ≥ vs. &lt; 65) and incompleteness of the planned treatment had also significant negative effect on both OS and DFS. Charlson co-morbidity index (≥4 vs. 0-3) was not associated with the difference of OS or DFS. After adjusting with multivariable analysis, Arm C still showed worse OS (HR 1.609, 95% CI, 1.339-1.934, p &lt; 0.0001) and DFS (HR 1.552, 95% CI, 1.333-1.807, p &lt; 0.0001) compared to Arm S. Conclusions: Both S-1 and CAPOX showed excellent efficacy. This nation-wide cohort study suggests that S-1 can be a better option in some clinical situations.
T cell engager (TCE) score in patients treated with bispecific CD3 TCE in phase I clinical trials.
Authors: Noé Herbel, Vincent Goldschmidt, Jean-Marie Michot, Ariane Laparra, Arthur Geraud, Kaissa Ouali, Francois-Xavier Danlos, Perrine Vuagnat, Alice Bernard-Tessier, Anas Gazzah, Rastilav Bahleda, Antoine Hollebecque, Aurelien Marabelle, Sophie Postel-Vinay, Yohann Loriot, Christophe Massard, Vincent Ribrag, Santiago Ponce Aix, Stephane Champiat, Capucine Baldini
Journal: Journal of Clinical Oncology (2023)

2573 Background: Immune prognostic scores, such as the Gustave Roussy Immune (GRIM) score have been investigated in patients (pts) treated with immune check-point blockers. We aimed to determine whether we could improve the selection of pts that could benefit from new immunotherapies such as bispecific CD3 T cell engagers (TCE) antibodies in pts treated in phase I clinical trials (CT), by building a new prognostic score. Methods: All patients treated with bispecific CD3 TCE in phase I CT from July 2018 to February 2023 at the Drug Development Department at Gustave Roussy were enrolled in the study. Univariate and multivariate analyses (UVA and MVA) were conducted on demographic, clinical and biological data to assess their prognostic value on progression free survival (PFS). MVA results were used to build a new prognostic score (TCE score). This score was then validated on overall survival (0S). The predictive ability (on PFS and OS) of the TCE score was assessed using Harrell’s C index. It was compared with the GRIM and Royal Marsden Hospital (RMH) scores predictive ability on PFS and OS. Results: A total of 67 patients (47 men, 20 women) with metastatic solid cancer or advanced hematological cancer were included. Median age was 62 years old. The most represented tumor types were prostate cancer (33%), lymphoma (25%) and small cell lung carcinoma (24%). UVA on PFS showed that elevated C-reactive protein (CRP) (HR: 2,36; 95%CI: 1,35-4,16; p = 2.10 -3 ) and lactate dehydrogenase (LDH) (HR: 3,00; 95%CI: 1,63-5,53; p = 2.10 -4 ) were associated with a worst PFS. In MVA, LDH (HR: 2,49; 95% CI: 1,30-4,74, p = 1.10 -4 ) and CRP levels (HR: 1,92; 95% CI: 1,1-3,46; p = 1.10 -4 ) were independent negative prognostic factors for PFS. The TCE score was based on MVA results (CRP&gt;10g/l: +1; LDH &gt; 250U/l: +1). It showed that pts with a high score (1-2) had a shorter PFS (median PFS: 2,8 months) and OS (median OS: 9,9 months) than low score (0) pts (median PFS: 5,8 months; median OS: not reached). TCE score’s Harrell’s C index for PFS was 0,63 and 0,64 for OS. For GRIM and RMH scores, Harrell’s C index for PFS were respectively 0,60 and 0,55. For OS it was respectively 0,58 and 0,53. Conclusions: To select patients for Bispecific CD3 TCE phase I CT, we built a new prognostic score, based on LDH and CRP levels, that can be used as prognostic of PFS and OS. TCE score is more reliable than GRIM and RMH scores to prognose PFS and OS.